A typical rheumatic disease--chronic rheumatoid arthritis (hereinafter RA)--is a systemic disease of connective-tissue having a main symptom of polyarthritis chronica, and is one of the autoimmune diseases. The general disease type thereof is polyarthritis which is progressive and chronic. It includes various clinical types such as one showing spontaneous remission, one showing highly progressive destruction and absorption of joints (e.g., arthritis dissecans) and the like. Clinical symptoms thereof include arthritis, swelling of joint, pain, deformation, morning stiffness, rheumatoid nodule, angiitis and the like.
For internal therapy of RA at present, nonsteroidal antiinflammatory agents (e.g., aspirin, indometacin, diclofenac sodium, ibuprofen, loxoprofen sodium, piroxicam, ampiroxicam, naproxen, and the like), adrenocorticosteroidal agents (e.g., intraarticular injection and oral administration of prednisolone, and the like), immunomodulators (e.g., gold preparation, D-penicillamine, bucillamine, actarit and the like), immunosuppressive agents (e.g., methotrexate, mizoribine and the like), and the like are used. These medicaments, nevertherless, fail to provide sufficient therapeutic effects, but rather, cause various side effects. For example, nonsteroidal antiinflammatory agents may cause peptic ulcer, nephropathy, hepatopathy and the like, adrenocorticosteroidal agents may induce and exacerbate infectious diseases, diabetes, moon face, peptic ulcer, adrenocortical insufficiency, thrombophlebitis, osteoporosis and the like, immunomodulators may cause dermatopathy, nephropathy, stomatitis and the like, and immunosuppressive agents may cause hepatopathy, leukopenia, thrombocytopenia and the like, some of which constituting severe side effects.
Typical allergic dermatitis includes contact dermatitis, atopic dermatitis and the like.
The contact dermatitis is an inflammation of the skin, which is developed by the contact of a substance with the skin. The onset of the disease is seen when, for example, a certain substance, such as a plant (e.g., lacquer and the like), cosmetics, a detergent, clothes, commercially available external drug and the like, comes into contact with the skin and when the substance shows irritation property beyond the resistance threshold value of the individual or when the individual has been sensitized with the substance in contact. The onset of the contact dermatitis is caused by physicochemical properties of the substance, sensitization activity, contact frequency, disposition of the individual and the like. The disease type includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis, contact urticaria, systemic contact-type dermatitis and the like. The clinical symptoms of contact dermatitis include acute eczema accompanied by erythema, edema, papula, vesicle, erosion, itching and the like, and repetition thereof develops eczema accompanying lichenification and infiltration. The mechanism of the onset of these diseases is considered to be associated with a type IV allergic reaction (delayed type allergic reaction) caused by T cell. The type IV allergic reaction is induced by the reaction of sensitized T cell with antigen, which releases lymphokine from the sensitized T cell to cause cytotoxicity and the like, which in turn induces this allergic reaction.
The atopic dermatitis is developed by exogeneous disposition, namely, by various antigens, since the subject has an atopic disposition of hypersensitivity against a certain substance. The clinical symptoms include marked itching, skin hypertrophy, infiltration, lichenification and the like. The mechanism of the onset of this disease has been said to include a type I allergic reaction (immediate hypersensitivity) involving IgE, but it is inconclusive. In recent years, a type IV allergic reaction has been considered to be responsible for the onset of this disease, and in fact, the clinical symptoms of this disease are extremely similar to the symptoms of the above-mentioned contact dermatitis allegedly caused by a type IV allergic reaction.
Currently, anti-histamine agents and steroidal agents have been used as therapeutic agent for contact dermatitis, and these and a part of the so-called antiallergic agents have been mainly used for atopic dermatitis.
Examples of the anti-histamine agents include diphenhydramine hydrochloride, mequitazine, promethazine hydrochloride, chlorpheniramine maleate and the like, and they have been mainly used to reduce itchiness.
As the steroidal agents, prednisolone, hydrocortisone butyrate, dexamethasone valerate, betamethasone dipropionate, clobetasol propionate and the like have been used. While these show therapeutic effects, they also cause side effects of induced infection, secondary adrenal cortical insufficiency, diabetes, peptic ulcer, hirsutism, alopecia, pigmentation and the like, and they are remotely desirable therapeutic agents.
As the antiallergic agent, tranilast, ketotifen fumarate, oxatomide, azelastine hydrochloride and the like have been used. None of them shows satisfactory therapeutic effects and they are not used for contact dermatitis.
In general, conventional so-called antiallergic agents, such as tranilast, oxatomide, pemirolast potassium, repirinast, emedastine difumarate, epinastine hydrochloride and the like, are either ineffective or fail to show satisfactory therapeutic effects on contact dermatitis and atopic dermatitis that are considered to be mainly caused by a type IV allergic reaction. This is postulated to be due to the inhibitory action of these so-called antiallergic agents only on type I allergic reaction (immediate hypersensitivity), in which IgE is involved, and a failure to show a type IV allergic reaction-inhibitory action (Kobayashi, K. et al.:Japan. J. Pharmacol. 63, 73-81 (1993), Takemori Omori et al.: Folia Pharmacol. Jpn. 80, 261-270 (1982), Yanagihara, Y. et al.: Japan. J. Pharmacol. 51, 93-100 (1989), Kazuo Takahashi et al.: Folia Pharmacol. Jpn. 88, 245-254 (1986), TadayukiSaito et al.: Folia Pharmacol. Jpn. 89, 55-62 (1987), Kamei, C. et al.:Arzneim.-Forsch./Drug Res.41(II), 1150-1153).
Hence, a type IV allergic reaction-inhibitory action at the inflammation site is considered to be essential for the treatment of allergic dermatitis, particularly contact dermatitis and atopic dermatitis.
In the above-mentioned various situations, the development of an antirheumatic agent effective for the alleviation and inhibition of the symptoms of RA and associated with less side effects, and a highly safe and highly effective therapeutic agent for allergic dermatitis, in which a type IV allergic reaction is involved, particularly a therapeutic agent for contact dermatitis and a therapeutic agent for atopic dermatitis, have been demanded.